Phase I/II Adaptive Randomized Trial of Bevacizumab Versus Bevacizumab Plus Vorinostat in Adults With Recurrent Glioblastoma

* INCLUSION CRITERIA: Patients will be included in the study based on the following criteria. * Patients must have histologically proven glioblastoma, gliosarcoma or anaplastic glioma to be eligible for the Phase I component of this protocol. Anaplastic gliomas include anaplastic astrocytoma (AA), anaplastic oligodendroglioma (AO), anaplastic mixed oligoastrocytoma (AMO), or malignant glioma NOS (not otherwise specified). Patients will be eligible if the original histology was low-grade glioma and a subsequent histological diagnosis of a malignant glioma is made. Only patients with histologically proven or imaging proven recurrent glioblastoma or gliosarcoma will be eligible for the Phase II component. Wafer acceptable if recurrence is confirmed. * All patients must sign an informed consent indicating their awareness of the investigational nature of this study. Patients must have signed an authorization for the release of their protected health information. * Patients must be 18 years old or older. * Patients must have a Karnofsky performance status (KPS) equal or greater than 60 * At the time of registration: * Patients must have recovered from the toxic effects of prior therapy to \< grade 2 toxicity per CTC version 4 (except deep vein thrombosis ) 1. 28 days from any investigational agent, 2. 4 weeks (28 days) from prior cytotoxic therapy, 3. 2 weeks (14 days) from vincristine, 4. 6 weeks (42 days) from nitrosoureas, 5. 3 weeks (21 days) from procarbazine administration, 6. greater than or equal to1 week (7 days) for non-cytotoxic agents, e.g., interferon, tamoxifen, thalidomide, cis-retinoic acid, etc. (radiosensitizer does not count). * Patients who receive anticancer agents for non-therapeutic purposes unrelated to this study (such as presurgically for obtaining pharmacology data for the agent) will be eligible to enter the study provided they have recovered from the toxic effects of the agent if any. Any questions related to the definition of noncytotoxic agents should be directed to the Study Chair. * Patients must have adequate bone marrow function (ANC greater than or equal to 1,500/mm3, platelet count of greater than or equal to 100,000/mm3), adequate liver function (SGPT less than or equal to 3 times upper limit normal and alkaline phosphatase less than or equal to 2 times upper limit normal, total bilirubin less than or equal to 1.5mg/dl, Patients with high bilirubin levels related to known diagnosis of benign hyperbilirubinemia (Gilbert s syndrome) will be eligible ., and adequate renal function (BUN less than or equal to 1.5 times institutional normal and Creatinine \< 1.5 mg/dl) prior to registration. These tests must be performed within 14 days prior to registration. * Patients must have shown unequivocal evidence for tumor progression as determined by an MRI scan done prior to study entry which will be reviewed by the treating physician to confirm and document recurrence. Patients with prior therapy that included interstitial brachytherapy or stereotactic radiosurgery must have confirmation of true progressive disease rather than radiation necrosis using the local institutional standards for such determination including advanced imaging or surgery. * The baseline on-study MRI scan should be performed within 14 days (+ 3 working days) prior to registration but before starting treatment and on a steroid dose that has been stable or decreasing for at least 5 days. If the steroid dose is increased between the date of imaging and registration (or at that time), a new baseline MRI is required. The same type of scan, i.e., MRI must be used throughout the period of protocol treatment for tumor measurement. * Patients having undergone recent resection of recurrent or progressive tumor will be eligible as long as all of the following conditions apply: 1. At least 4 weeks (28 days ) have elapsed from the date of surgery and the patients have recovered from the effects of surgery. 2. Evaluable or measureable disease following resection of recurrent Malignant Glioma is not mandated for eligibility into the study. 3. To best assess the extent of residual disease post-operatively, a MRI should be done no later than 96 hours in the immediate post-operative period or at least 4 weeks post-operatively, within 14 days prior to registration. If the 96-hour scan is more than 14 days before registration, the scan needs to be repeated. If the steroid dose is increased between the date of imaging and registration, a new baseline MRI is required on a stable steroid dosage for at least 5 days. * Patients must have failed prior radiation therapy and must have an interval of greater than or equal to 12 weeks (84 days) from the completion of radiation therapy to study entry except if there is unequivocal evidence for tumor recurrence (such as histological confirmation or advanced imaging data such as PET scan) in which case at least 4 weeks (28 days) from completion of radiation therapy will suffice. * Patients with prior therapy that included interstitial brachytherapy or stereotactic radiosurgery must have confirmation of true progressive disease rather than radiation necrosis based upon either PET or Thallium scanning, MR spectroscopy or surgical/pathological documentation of disease. * Women of childbearing potential must have a negative B-HCG pregnancy test documented within 14 days prior to registration. Women of childbearing potential must not be pregnant, must not be breast-feeding, and must practice adequate contraception for the duration of the study, and for 30 days after the last dose of study medication. Patients must not be pregnant because animal studies show that bevacizumab and Vorinostat are teratogenic. * Male patients on treatment with Vorinostat must agree to use an adequate method of contraception for the duration of the study, and for 30 days after the last dose of study medication. * Patient must be able to tolerate the procedures required in this study including periodic blood sampling, study related assessments, and management at the treating institution for the duration of the study. * Patients receiving treatment with any antiepileptic medications except Valproic acid (because of its HDAC inhibitory activity) can be included in the study. Vorinostat is not metabolized by Cytochrome P450 3A4 (CYP 3A4); however, Vorinostat may potentially suppress CYP 3A4 activity. Therefore, patients should preferably be treated with nonenzyme inducing anti-epileptic medications although this is not mandatory. If enzyme inducing antiepileptic drugs are used, monitoring of these drug levels should be considered, as considered clinically appropriate by the treating physician. * For the Phase II portion of the study, patients may have had treatment for no more than 2 prior relapses. There is no limit to the number of relapses for the phase I portion of the study provided the functional status and other eligibility criteria for enrollment are met. Relapse is defined as progression following initial therapy (i.e. radiation+/- chemo if that was used as initial therapy). The intent therefore is that patients had no more than 3 prior therapies (initial and treatment for 2 relapses). If the patient had a surgical resection for relapsed disease and no anti-cancer therapy was instituted for up to 12 weeks, and the patient undergoes another surgical resection, this is considered as 1 relapse. For patients who had prior therapy for a low-grade glioma, the surgical diagnosis of a high-grade glioma will be considered the first relapse EXCLUSION CRITERIA: General Exclusion Criteria * Inability to comply with protocol or study procedures (for example, an inability to swallow tablets). * Prior treatment with bevacizumab or Vorinostat. * Patients receiving valproic acid (VPA), an anticonvulsant drug with HDAC inhibitor properties, will be excluded, unless they are switched to an alternative agent prior to treatment initiation. A 5-day wash out period is required. Patients who have failed prior treatment with other histone deacetylase inhibitors will be excluded. * Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from providing informed consent. * Any condition, including the presence of clinically significant laboratory abnormalities, which places the patient at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret data from the study. These would include 1. Active infection (including persistent fever) including known AIDS or Hepatitis C infection 2. Diseases or conditions that obscure toxicity or dangerously alter drug metabolism 3. Serious intercurrent medical illness (e.g. symptomatic congestive heart failure). * Current, recent (within 4 weeks (28 days) of the first infusion of this study, or planned participation in an experimental antitumor drug study (other than the current one). * Patients with a history of any other cancer (except non-melanoma skin cancer or carcinoma in-situ of the cervix or bladder), unless in complete remission and off of all therapy for that disease for a minimum of 3 years are ineligible. * Patients with spinal disease (metastasis) and/or leptomeningeal disease will not be allowed in the study. Bevacizumab-Specific Exclusion Criteria * Inadequately controlled hypertension (defined as systolic blood pressure \> 140 mmHg and/or diastolic blood pressure \> 90 mmHg). * Prior history of hypertensive encephalopathy. * New York Heart Association (NYHA) Grade II or greater congestive heart failure. * History of myocardial infarction or unstable angina within 6 months prior to Day 1. * History of stroke or transient ischemic attack within 6 months prior to Day1. * Significant vascular disease (e.g., aortic aneurysm, requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior to Day 1. * History of hemoptysis (greater than or equal to 1/2 teaspoon of bright red blood per episode) within 1 month prior to Day 1. * Evidence of bleeding diathesis or significant coagulopathy (in the absence of therapeutic anticoagulation). * Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to Day 1 or anticipation of need for major surgical procedure during the course of the study. Patients with recent resection will be eligible for entry into the surgical arm of the study but will follow guidelines as in section 4.9 . * Core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 7 days prior to Day 1. * History of abdominal fistula or gastrointestinal perforation within 6 months prior to Day 1. * Serious, non-healing wound, active ulcer, or untreated bone fracture. * Proteinuria as demonstrated by: * Urine protein: creatinine (UPC) ratio greater than or equal to 1.0 at screening OR * Urine dipstick for proteinuria greater than or equal to 2+ (patients discovered to have greater than or equal to 2+ proteinuria on dipstick urinalysis at baseline should undergo a 24 hour urine collection and must demonstrate less than or equal to 1g of protein in 24 hours to be eligible). * Known hypersensitivity to any component of bevacizumab. * Pregnancy (positive pregnancy test) or lactation. Use of effective means of contraception (men and women) in subjects of child-bearing potential is required for study treatment.